The recent success in reprogramming somatic cells into induced Pluripotent Stem (iPS) cells by defined factors has opened exciting possibilities not only for the investigation of complex human diseases in the Petri dish but also for the ultimate application in transplantation therapy. Direct reprogramming provides for the first time the opportunity to generate in vitro and in vivo models of complex disorders such as familial and sporadic Parkinson's disease using patient-specific cells. The experiments proposed in this application are aimed at using the iPS technology to set up an experimental system to study a human genetic disease of the hematopoietic system. The proposal has three aims: 1. Derivation of iPS cells from peripheral blood: We will establish protocols to isolate iPS cells from myeloid cells of human peripheral blood using vectors that can be deleted by transient Cre expression. 2. Characterization of iPS cell-derived hematopoietic cells (HSCs): We will establish robust protocols allowing in vitro differentiation of iPS cell-derived HSCs and assess their potential to engraft in NOD/SCID mice. To improve engraftment efficiency we will precondition the cells by transient expression of reprogramming factors or oncogenes. 3. Biology and genetics if myeloproliferative neoplasm (MPN): We will establish an experimental paradigm to study the biology and genetic predisposition of myeloproliferative neoplastic disorder (MPN), a disorder characterized by a specific JAK2 mutation. The methods developed in aims 1 and 2 will be used to investigate the pathology of MPN such as assessing whether the JAK2 mutation provides a selective advantage to the growth of hematopoietic cells and whether hematopoietic stem cells derived from skin biopsies of the same patient acquire the mutation when differentiated in vitro or when transplanted into NOD/SCID mice.